Chronic inflammatory demyelinating polyneuropathy (CIDP) is considered the peripheral counterpart of multiple sclerosis because of some similarities in their immunopathogenesis and course of illness. The B7/CD28:CTLA-4 costimulatory pathway plays an important role in the regulation of immune responses in both diseases. Elimination of B7-2 in the nonobese diabetic (NOD) mouse prevents the development of diabetes, but leads to the development of a spontaneous autoimmune polyneuropathy (SAP) mimicking CIDP. This unique model provides an opportunity to study the molecular mechanisms involved in the pathogenesis of inflammatory neuropathies. We found that SAP is mediated by Th1 response to myelin P0, but possible contribution of autoantibodies cannot be excluded. In Aim1, we will determine whether anti-P0 antibodies contribute to the development or progression of SAP, and if so, delineate the fine relationship between antibody specificity and pathogenicity. In Aim2, we will investigate whether elimination of B7-2 leads to age- dependent perturbations in regulatory mechanisms, particularly with regards to CD4+ vs CD8+ regulatory T cells. In Aim3, we will delineate the functional consequences of B7-2 elimination on dendritic cells, including their ability to prime T cells, their migratory properties, and their potential interaction with Schwann cells. These proposed studies will enhance our understanding of the pathogenesis of inflammatory neuropathies, and the mechanisms involved in the protean manifestations of autoimmunity as a result of perturbations in co-stimulatory molecules. Findings from these experiments will also have implications for therapy aimed at correcting the ensuing impairment in dendritic cell function or regulatory mechanisms. PUBLIC HEALTH RELEVANCE: In the non-obese diabetic (NOD) mouse, elimination of a co-stimulatory molecule B7-1 expressed by antigen-presenting cells makes diabetes worse, while elimination of a related molecule B7-2 prevents the development of diabetes but triggers the development of an inflammatory neuropathy. We have recently identified myelin protein zero (P0) as one of the antigens targeted by T cells in this model, though antibodies to P0 are also detected in animals with neuropathy. In this proposal, we plan to investigate further the immune mechanisms contributing to development or progression of the inflammatory neuropathy, including the role of antibodies, defect in regulatory mechanisms, and perturbations in the function of dendritic cells;the latter belong to the group of antigen-presenting cells.